The binding sites for ethidium bromide and 9-aminoacridine to DNA, which are responsible for their biological effects, will be determined using a photoaffinity labeling technique and radioactive drug analogs. Mutagenesis specific in Salmonella tester strains can be correlated with binding in intact cells, since the photosensitive analogs can be activated in situ with subsequent isolation and characterization of the resultant in vivo drug-DNA association. Techniques such as CsCl density gradient ultracentifugation, enzymatic and chemical degradation, heat denaturation, UV-VIS, and NMR spectroscopy, acrylamide gel electrophoresis and other chromatographic techniques will be utilized to determine the specific mode of interaction. Studies will establish the relationship between binding of different drug analogs and their biological consequences. Model complexes from isolated DNA and synthetic nucleotides will be compared and drug-dinucleotide interactions will be analyzed by x-ray crystallography and NMR spectroscopy. These studies using two classic drugs which interact with DNA will serve to enhance our understanding of drug binding and drug action which will be useful in cancer chemotherapy, the treatment of viral and bacterial infections, and parasitic diseases.